Abstract
Caveolin-1 is a transmembrane protein with both tumor promoter and suppressor functions that remain poorly understood. Cav1 phosphorylation by Src kinase on tyrosine 14 is closely associated with focal adhesion dynamics and tumor cell migration, however the role of pCav1 in vivo in tumor progression remains poorly characterized. Herein, we expressed phosphomimetic Y14D, wild type, and non-phosphorylatable Y14F forms of Cav1 in MDA-MB-435 cancer cells. Expression of Cav1Y14D reduced cell proliferation and induced the TP53 tumor suppressor. Ectopic expression in MDA-MB-435 cells of Y14 phosphorylatable Cav1 was required for induction of TP53 in response to oxidative stress. Cav1Y14D promotes an apparent reversal of the Warburg effect and markedly inhibited tumor growth in vivo. However, Cav1 induced pseudopodial recruitment of glycolytic enzymes, and time-lapse intravital imaging showed increased invadopodia protrusion and extravasation into blood vessels for Cav1WT and Y14D but not for Y14F. Our results suggest that Cav1 Y14 phosphorylation levels play a role in the conflicting demands on metabolic resources associated with cancer cell proliferation versus motility.
Highlights
Caveolin-1 (Cav1) plays a complex role in cancer progression and has been ascribed both tumor promoter and suppressor functions; elevated Cav1 is associated with a poor prognosis in prostate, melanoma cancers and triple negative breast cancer [1, 2]
TP53 levels were increased in Cav1WT and Cav1Y14D relative to dsRed and Cav1Y14F transfected MDA-MB-435 cells (Figure 1B) and TP53 effectors p16, p21 and pRb were elevated in Cav1Y14D cells (Figure 1C); Cav1 protein levels in Cav1Y14D cells were elevated (Figure 1B), as we previously reported [22]
The dramatic effects observed here for Cav1Y14D on tumor growth presumably reflects a phenotype related to excessively high pCav1 levels, that are not observed here in Cav1WT cells, but could conceivably occur down-stream of oxidative or mechanical stress [13, 22, 37]
Summary
Caveolin-1 (Cav1) plays a complex role in cancer progression and has been ascribed both tumor promoter and suppressor functions; elevated Cav is associated with a poor prognosis in prostate, melanoma cancers and triple negative breast cancer [1, 2]. Cav induces premature senescence when over-expressed and is upregulated in aged fibroblasts [3]. Cav has been previously shown to induce TP53 expression [4, 5]. Cav deficiency has been reported to induce premature senescence via mitochondrial dysfunction [6], induce a switch from oxidative phosphorylation to glycolysis in response to oxidative stress [7] and mediate stromal cell regulation of mitochondrial metabolism of cancer cells [8]. Cav increases aerobic glycolysis in cancer cells and promotes liver regeneration through hepatic glycolysis [9,10,11]. Cav plays complex roles in the regulation of cancer cell metabolism [12]
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